The Micro-RNA 192 As an Effective Response Prediction Factor in the Multimodality Therapy of Locally Advanced Esophageal Cancer
Daniel Vallbohmer*1, Peter P. Grimminger1, Christoph Wandhoefer1, Jan Brabender1, Uta Drebber2, Elfriede Bollschweiler1, Arnulf H. HöLscher1, Ralf Metzger1, Magarethe Odenthal2
1Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany; 2Institute of Pathology, University of Cologne, Cologne, Germany
Background: Neoadjuvant multimodality treatment is frequently applied to improve the poor prognosis associated with locally advanced esophageal cancer. However, only patients with a major histopathologic response to neoadjuvant therapy seem to have a significant survival benefit. We have shown in a recent pilot study using microarray-technique that the expression profile of microRNAs depends significantly on the histopathologic response of patients with locally advanced esophageal cancer undergoing multimodality treatment. This study aimed to validate these identified single microRNAs by real-time PCR.Patients and Methods: Eighty-eight patients with locally advanced esophageal cancer (cT2-4, Nx, M0) were included in the study. All patients received neoadjuvant chemoradiation (cisplatin, 5-FU, 45 Gy) and subsequently underwent transthoracic en bloc esophagectomy. Histomorphologic regression was defined as major histopathological response when resected specimens contained less than 10% vital residual tumor cells (major response: 34 patients; minor response: 54 patients). Intratumoral microRNA was isolated from pretherapeutic tissue biopsies and corresponding surgical specimens. Based on the microarray results, the amplification profile of dysregulated microRNAs was analyzed and the microRNAs 192, 194 and 622 were selected for the further analysis of the validation population.Results: The expression of all three microRNAs was significantly reduced during neoadjuvant therapy, showing lower levels in post-therapeutic tumor samples (p<0.001). Furthermore, the pre-therapeutic intratumoral expression of microRNA 192 was significantly correlated with histopathologic response: patients with a major response had a significantly higher intratumoral microRNA 192 amount compared with patients having a minor response (p=0.01). Moreover, by using an expression cut-off value of 0.63, the sensitivity, specificity and accuracy of pre-therapeutic microRNA 192 for assessment of histopathologic response was 96%, 82% and 88% respectively (p=0.05).Conclusion: Our data support the role of micro RNA 192 as a predictive marker for therapy response in the multimodality therapy of patients with locally advanced esophageal cancer. In a multi-institutional trial we will now try to confirm these results.
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